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Wnt regulates amino acid transporter Slc7a5 and so constrains the integrated stress response in mouse embryos
Author(s) -
Poncet Nadège,
Halley Pamela A,
Lipina Christopher,
Gierliński Marek,
Dady Alwyn,
Singer Gail A,
Febrer Melanie,
Shi YunBo,
Yamaguchi Terry P,
Taylor Peter M,
Storey Kate G
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948469
Subject(s) - biology , integrated stress response , wnt signaling pathway , microbiology and biotechnology , morphogenesis , amino acid transporter , embryo , transcriptome , gene expression , signal transduction , transporter , genetics , gene , messenger rna , translation (biology)
Amino acids are essential for cellular metabolism, and it is important to understand how nutrient supply is coordinated with changing energy requirements during embryogenesis. Here, we show that the amino acid transporter Slc7a5 / Lat1 is highly expressed in tissues undergoing morphogenesis and that Slc7a5 ‐null mouse embryos have profound neural and limb bud outgrowth defects. Slc7a5 ‐null neural tissue exhibited aberrant mTORC1 activity and cell proliferation; transcriptomics, protein phosphorylation and apoptosis analyses further indicated induction of the integrated stress response as a potential cause of observed defects. The pattern of stress response gene expression induced in Slc7a5 ‐null embryos was also detected at low level in wild‐type embryos and identified stress vulnerability specifically in tissues undergoing morphogenesis. The Slc7a5‐ null phenotype is reminiscent of Wnt pathway mutants, and we show that Wnt/β‐catenin loss inhibits Slc7a5 expression and induces this stress response. Wnt signalling therefore normally supports the metabolic demands of morphogenesis and constrains cellular stress. Moreover, operation in the embryo of the integrated stress response, which is triggered by pathogen‐mediated as well as metabolic stress, may provide a mechanistic explanation for a range of developmental defects.